The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

High risk with carboplatin. Hypersensitivity risk increases with number of cycles of carboplatin.

Antiemetics for multi-day protocols

Antiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be required.

A NK1 receptor antagonist and a 5HT3 receptor antagonist in combination with dexamethasone are available on the PBS for primary prophylaxis of carboplatin induced nausea and vomiting.

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Hydration regimen pre high dose cyclophosphamide or ifosfamide (as per local guidelines).
There is limited evidence and no consensus regarding hydration regimens and mesna dose, route or timing of administration.

G-CSF (filgrastim, lenograstim, lipegfilgrastim or pegfilgrastim) is available on the PBS for the primary prevention of neutropenia.

This protocol may be used for mobilisation of peripheral blood haematopoietic stem cells. The dose of filgrastim for mobilisation is 10 micrograms/kg/day in divided doses and should be commenced from day +4 after the last cycle of chemotherapy.

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note: All dose reductions are calculated as a percentage of the starting dose

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.

Digoxin

Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin

Monitor digoxin serum levels; adjust digoxin dosage as appropriate

Antiepileptics

Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity

Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy

Diminished response to vaccines and increased risk of infection with live vaccines

Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

Day 2

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Prime IV line(s).

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

Prophylaxis medications

Patient information

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)

Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

An inflammatory process, characterised by diffuse mucosal inflammation with haemorrhage involving the entire bladder. Patients are at risk following treatment with cyclophosphamide, ifosfamide and radiotherapy.

Ifosfamide induced encephalopathy has been reported in 10 to 30% of patients receiving high dose ifosfamide. Common symptoms include confusion, ataxia, weakness, seizures, somnolence and hallucinations. Onset may be 2 to 48 hours after commencing treatment. When reversible, symptoms usually resolve within 1 to 3 days.

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiotherapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

A search of the literature did not find strong evidence to support the use of fractionated or infusional ICE for the treatment of Hodgkin lymphoma. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the Phase II studies by Moskowitz et. alr and Hertzberg et. al.r

The combination of ifosfamide, carboplatin and etoposide (ICE) as salvage chemotherapy for relapsed/refractory Hodgkin lymphoma was originally studied prospectively in a phase 2 study in the 1990s. 65 consecutive patients (43 relapsed, 22 refractory) were treated with ICE salvage followed by, in responders, high-dose therapy and autologous stem cell transplant +/- radiation. The ICE protocol administered included ifosfamide given as an infusion over 24 hours and required patients to be admitted to hospital. Two cycles of ICE were given with 2 weeks between cycles.r

ICE may also be given in the outpatient setting, with the dose of ifosfamide split over 3 days (fractionated) and the cycles administered every 21 days. In a study of the fractionated regimen, 13 of the patients had Hodgkin lymphoma (11 relapsed, 2 refractory). A total of 2 cycles of ICE were planned followed by high-dose therapy and autologous stem cell transplant.r

Both the infusional and fractionated ICE regimens appear to be to be effective for salvage and stem cell mobilisation in Hodgkin lymphoma.

Source

Study & Year Published

Supports Use

Is the dose and regimen consistent with the protocol?

Comments

Phase II trials

Moskowitz et al. 2001

Yes

N/A

N/A

Hertzberg et al. 2006

Yes

Yes

-

Case series

N/A

N/A

N/A

-

Observational studies

N/A

N/A

N/A

-

Guidelines

Date published/revised

Supports Use

Is the dose and regimen consistent with the protocol?

Comments

NCCN

03/03/14

Yes

N/A

-

BCCA

N/A

N/A

N/A

-

CCO

N/A

N/A

N/A

-

Efficacy

Infusional

The response rate in the study of infusional ICE was 88% (CR 17, PR 38 out of 65 patients). The median interval between the 2 cycles was 16 days (range, 13-28) with 23/65 patients receiving therapy on schedule. 56 of the 57 responders proceeded to autologous transplantation and the event-free survival (EFS) and overall survival (OS) for responders were 68% and 83%, respectively, at 43 months (see graph below).r

Fractionated

In the study of fractionated ICE, all 13 patients with Hodgkin lymphoma responded (31% CR, 69% PR) and proceeded to transplant. The EFS was 69% and OS 85% at 30 months follow up. Mobilisation of PBSC following fractionated ICE was successful with the majority of patients requiring only one leukapheresis procedure.r

Toxicity

There were no toxic deaths in either the infusional or fractionated ICE studies. The toxicities in the infusional studyr are not fully described but the same group also published a study of ICE salvage in 163 patients with non-Hodgkin lymphoma.r In this group, thrombocytopenia was the dose limiting toxicity with grade 3/4 thrombocytopenia occurring in 29% of cycles given and 30% of patients requiring platelet transfusion. 13% of cycles were complicated by grade 4 neutropenia requiring hospital admission. The neutrophil nadir occurred 7 to 9 days after the beginning of the cycle. Anaemia was a common occurrence with 98 patients requiring red cell transfusions. Non-haematological toxicities were uncommon and included gross haematuria in 4 of 381 cycles, one case of reversible nephrotoxicity, two cardiac toxicities (congestive cardiac failure & supraventricular tachycardia) and 5 cases of neurological toxicity (1 peripheral neuropathy and 4 confusion due to ifosfamide-induced encephalopathy). The patients with cardiac toxicity and encephalopathy were not retreated with ICE.r

The major toxicities reported in the fractionated ICE study (which included 75 patients with non-Hodgkin and Hodgkin lymphoma) were haematological with grade 4 thrombocytopenia in 51% and grade 4 neutropenia in 55%. The neutrophil nadir occurred between days 9 and 11 post-therapy and was brief however 18 patients developed neutropenic sepsis requiring hospital admission. Non-haematological toxicities included 2 cases of CNS toxicity (grade 1 & 2), one case of haematuria and one case of (reversible) nephrotoxicity. Two patients developed cardiac complications with one case of atrial fibrillation and another of worsening cardiac failure.r

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Reviewed by Haematology Reference Committee with no significant changes, review in 2 years

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au